Figure 32. The mammalian UPRmt axes. Various UPRmt activators initiate gene expression via the ATF4/5, Erα, and SIRT3 branches. Triggered signaling pathways lead to a number of mitoprotective outcomes aimed at restoring mitochondrial homeostasis. ATF4/5, activating transcription factor 4/5; ERα, estrogen receptor alpha; DRP1, dynamin-related protein 1; FIS1, mitochondrial fission 1 protein; FOXO3, forkhead box protein O3; HTRA2, HtrA serine peptidase 2; MFN2, mitofusin 2; NRF1, nuclear respiratory factor 1; OPA1, mitochondrial dynamin-like GTPase; PGC1α, peroxisome proliferator-activated receptor-gamma coactivator-1 α; SIRT3, sirtuin 3; TFAM, mitochondrial transcription factor A.
The upregulation of mitochondrial chaperones and co-chaperones, mainly the group of heat shock proteins (e.g., Hsp60, Hsp70, Hsp10, HSC20, DNAJA3) and proteases (e.g., HtrA2, ClpP, Lonp1), constitutes the strongest cell response to stress. The Hsp response is predominantly cytoprotective because chaperones have the potential to attenuate pathology by the clearance of aggregated proteins, e.g., amyloid proteins. They also prevent further aggregation by inhibiting the nucleation and elongation processes of cross-seeding and facilitating cellular repair and defense mechanisms
[38]. In DM, the Hsp-response is weakened and was shown to positively correlate with dysfunctional insulin signaling. In this mechanism, DM-associated increases in glucose synthase kinase-3 activity lead to abnormal phosphorylation of heat shock transcriptional factor 1 (Hsf1). Phosphorylated Hsf1 is less efficient at binding to the Hsp-transcription element and quenching the stress-induced transcriptional activity, decreasing the level of Hsp proteins
[39]. The downregulation of the mitochondrial chaperone Hsp60 due to a lack of leptin signaling has been shown to be sufficient to induce hypothalamic insulin resistance in a T2DM murine model
[40]. In the model of high fat diet-induced hypothalamic insulin resistance, a disrupted mitochondrial stress response led to mitochondrial dysfunction, excessive autophagy, and increased weight gain. Short-term intranasal insulin application restored expression of Atf4, Chop, Hsp60, Hsp10, ClpP, and Lonp1, suggesting that hypothalamic insulin/IGF1 signaling regulates mitochondrial stress response and ensures proper mitochondrial function
[41]. Reduction in co-chaperone Hsp10, which modulates Hsp60 activity, was also sufficient to cause hypothalamic insulin resistance with acute liver insulin resistance, decreases in subunit protein levels of the ETC complexes, and mitochondrial dysfunction in T2DM mice. Interestingly, Hsp10 knockdown in murine hypothalamic cells increased saturated fatty acids (FA) and decreased monounsaturated FA content
[42]. The shift from unsaturated FAs to saturated FAs in cardiolipin, the inner mitochondrial membrane phospholipid essential for the proper function of the respiratory enzymes and the assembly of the ETC into supercomplexes, was also observed in the brain cortex of streptozotocin-rats
[19]. Elevated saturated FAs were also reported in patients with Hsp60 deficiency, metabolic syndrome, and in the cerebrospinal fluid of humans with obesity
[43][44]. It is currently unclear how Hsp interferes with FA metabolism.
Several studies have also suggested a link between mitochondrial stress and neuroinflammation via Hsp60′s interaction with Toll-like receptors, which leads to the production of proinflammatory mediators, such as TNF-α, IL-1β, IL-6, and IL-8
[45][46]. Hyperglycemia-linked neuroinflammation in the CNS plays a key role in the development of vascular dementia in diabetic patients. Of note, Hsp60 holds many functions and occurs not only inside mitochondria but also in other intracellular locations, and it may be released from a cell too. Extracellular secretion of Hsp60 via exomes, which play an important role in cell-to-cell communication, has been documented in various inflammatory diseases including DM, suggesting that neuroinflammation could spread to neighboring neuronal cells, such as astrocytes
[47][48].
Neuroinflammatory processes, a result of mitochondrial impairment, were also noticed in the model of metabolic syndrome (MS), a precondition for obesity, DM, and cardiovascular diseases. An important feature of MS is the deficiency of silent information regulator sirtuin 3 (Sirt3), the mitochondrial member of the group of NAD+-dependent lysine deacetylases. Deacetylases control a wide range of cellular processes, among them, Sirt3 controls energy metabolism processes, antioxidant defense, and mitochondrial dynamics
[49]. The importance of sirtuins for cell homeostasis is highlighted by their engagement in the UPRmt stress response axis. In the brain of mice with MS, Sirt3 deficiency led to impaired mitochondrial respiration, downregulation of mitochondrial fission proteins Mfn1, Mfn2, elevated levels of brain IL-1β, and inflammasome formation
[50]. Sirt3 deficiency-induced hyperacetylation of the mitochondrial proteome was also shown to spoil glucose metabolism, preferentially at the Krebs cycle, disarrange metabolic coupling between neurons and astrocytes, and decrease neurotransmitter synthesis
[51]. In the mouse model of comorbid Alzheimer’s disease with amyloid pathology and MS, Sirt3 deficiency aggravated insulin resistance, glucose intolerance, amyloid plaque deposition, neuroinflammation, and microgliosis, suggesting that MS may interact with amyloid pathology during the early cellular phase of Alzheimer’s disease
[52]. Thus, SIRT3 decline induced mitochondrial dysfunction and neuroinflammation in chronic metabolic diseases, such as DM, may be important participants in the cascade of molecular processes resulting in proteotoxic stress, neuronal cell damage, and late-life cognitive decline.
Healthy and fully functional mitochondria are maintained by unique equilibrium among the processes of mitochondrial biogenesis, removal of damaged mitochondria by mitophagy, and mitochondrial dynamics, which are regulated by mitofusins Mfn1, Mfn2, Drp1, and OPA1. Mitochondrial dynamics in the brain are associated with feeding, glucose homeostasis, and whole-body metabolism, and disorders of mitochondrial fission–fusion proteins are observed in obesity, DM, and neuroinflammation
[53]. Mfn1 has recently emerged as a nutrient sensor in POMC neurons that influences whole-body glucose metabolism as it plays a key role in the central control of insulin release
[54]. Drp1-mediated mitochondrial abnormalities have been linked to synaptic injury in the diabetic hippocampus
[55]. A clinical trial in patients with T2DM-related cognitive decline observed a decrease in mitochondrial copy number, indicating that decreased mitochondrial biogenesis occurs in DM patients
[56]. A decrease in the expression of PGC-1α (peroxisome proliferator-activated receptor-gamma coactivator), TFAM (mitochondrial transcription factor A), and NRFs (nuclear respiratory factors) in diabetic rat brains also corroborates dysfunctional mitochondrial biogenesis
[57]. As a result, DM-linked attenuation of mitochondrial biogenesis does not restore decreased mitochondrial mass following the autophagosomal degradation of damaged mitochondria by mitophagy and leads to exacerbation of cellular damage and decline in brain functional ability.